Premature Ovarian Insufficiency: Aetiology and Long-Term Consequences Review

WOMEN’S HEALTH

ISSN 2380-3940 http://dx.doi.org/10.17140/WHOJ-3-121 Open Journal Review Premature Ovarian Insufficiency: Aetiology *Corresponding author and Long-Term Consequences Naina Kumar, MD Associate Professor Department of Obstetrics and Gynecology Maharishi Markandeshwar Institute of Medical Sciences and Research Naina Kumar, MD*; Isha Manesh, MD Student Mullana-133207, Ambala, Haryana, India Tel. +91-9552515600 E-mail: [email protected] Department of Obstetrics and Gynecology, Maharishi Markandeshwar Institute of Medical Sciences and Research, Mullana-133207, Ambala, Haryana, India

Volume 3 : Issue 2 Article Ref. #: 1000WHOJ3121 ABSTRACT

Article History Premature ovarian insufficiency (POI) is characterised by premature cessation of ovulation/ Received: January 28th, 2017 menstruation for 4-6 months along with raised serum gonadotropin levels especially follicle Accepted: March 3rd, 2017 stimulating hormone (FSH) (>40 IU/L) on two or more occasions >4 weeks apart. POI is a Published: March 7th, 2017 heterogeneous disorder resulting from various autoimmune, iatrogenic and metabolic factors, chromosomal or genetic mutations and infections. Premature loss of ovarian function in women with POI is associated with long-term psychosocial sequelae, infertility and major health com- Citation plications. It is also associated with age-specific increase in mortality due to cardio-vascular Kumar N, Manesh I. Premature ovarian insufficiency: Aetiology and long- diseases. Its occurrence has increased in recent years as more and more women now-a-days at- term consequences. Women Health tain motherhood late, also there is increase in incidence of gynaecological malignancies and its Open J. 2017; 3(2): 45-58. doi: successful management leading to increased risk of POI. This manuscript aims to highlight the 10.17140/WHOJ-3-121 recent advances in pathogenesis and management of POI. Literature regarding premature ovarian insufficiency, its incidence, pathogenesis, management and recent advances was searched from various English language journals, WHO, ACOG data, published peer-reviewed articles on PubMed, Medline, Embase and Google Scholar upto 2017.

KEY WORDS: Amenorrhoea; Menopause; Ovary; Ovulation; Stem cells.

ABBREVIATIONS: POI: Premature Ovarian Insufficiency; FMR1; Fragile X mental retardation 1; WHO: World Health Organization; AOAs: Antiovarian antibodies; APSs: Autoimmune Polyendocrine Syndromes; FSH: Follicle Stimulating Hormone; BMPs: Bone Morphogenetic Proteins; ESCs: Embryonic Stem Cells; MSCs: Mesenchymal Stem Cells; UCMSCs: Umbili- cal Cord Mesenchymal Stem Cells; ADSCs: Adipose-derived Stem Cells; FMR-1:Fragile X Mental Retardation 1.

INTRODUCTION

Premature ovarian insufficiency (POI) also known as Premature ovarian failure or Hypergo- nadotropic ovarian failure or Menopausa precoce1 is defined as a primary ovarian defect, characterized by an absent menarche (primary amenorrhea) or premature loss of ovarian follicles before 40 years of age (secondary amenorrhea).2,3 Characteristic features include cessation of ovulation or amenorrhoea for 4 months or more, hypoestrogenism (estradiol levels <50 pg/ ml)4 and high serum gonadotropin levels,5,6 especially two serum follicle-stimulating hormone (FSH) levels (>4 weeks apart) in menopausal range7,8 (>40 IU/l).4

Copyright POI was previously known as premature menopause, but this term is a misnomer, as ©2017 Kumar N. This is an open all women with POI do not always stop menstruating, neither do their ovaries shut down com- access article distributed under the pletely.8 In most women aged >40 years, there is a physiological decline in ovarian function Creative Commons Attribution 4.0 with aging which is called as perimenopause/menopausal transition.9 Ovarian ageing resulting International License (CC BY 4.0), in ovarian failure and menopause is a continuous process5,10 and menopause is usually attained which permits unrestricted use, 11-13 distribution, and reproduction in at 51 years (range 40-60 years). The World Health Organization (WHO) defines menopause any medium, provided the original as permanent cessation of menstruation due to ovarian follicular activity loss.13 work is properly cited.

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POI differs from menopause as, in POI unpredictable Incidence and varying degrees of ovarian functions are still present in 50% of women, and about 5-10% can even conceive and deliver child POI is relatively common, with an estimated occurrence of 1 after diagnosis and treatment.7,8,14 It is a hypergonadotropic and in 100 by 40 years; 1 in 1000 by 30 years11,12 and 1 in 10,000 hypogonadism state resulting from depletion/dysfunction of by 20 years of age.1,20,21 It affects around 1-3% of women in the ovarian follicles due to either low initial numbers or acceler- reproductive age below 40 years and around 0.1% in women be- ated loss.15 Premature loss of ovarian function leads to signifi- low 30 years of age.2,10,18,22,23 Women with POI, around 10-28% cant long-term psychosocial sequelae and major health com- experience primary amenorrhea and 4-18% secondary amenor- plications.16 It also results in age-specific increase in mortality rhea.10,18 Incidence of spontaneous onset POI has increased due rate.17,18 to increasing success rates of cancer treatment in girls and young women.20,24,25 On the other hand, familial POI accounts for 15- Based on the age of onset, POI can present itself as 30% of all cases.1,12,26 primary amenorrhea, without onset of menarche, or secondary amenorrhea after puberty.3 It is a continuum of disorders with Pathogenesis four clinical states which are not permanent. Patients usually budge from one state to another in an unknown manner.19 These Process of human folliculogenesis being highly complex and or- states are as follows: ganised, is characterised by progressive maturation of small primordial follicles to larger ovulatory follicles. This whole process 27 1. Occult POI presents as unexplained infertility with normal occurs continuously, and can stretch over a period of a year. baseline serum FSH levels. Reproductive life span of human females start with a fixed number of primordial follicles,28 of which only 400-500 develop and 2. Biochemical POI presents as unexplained infertility with ovulate before physiological menopause (Figure 1).29 elevated basal serum FSH levels. 3. Overt POI previously known as premature ovarian failure is On the other hand, exact mechanism for development characterized by elevated serum FSH levels with associated of POI is not known. It can be due to: a) Preliminary decrease menstrual disorders like oligomenorrhea, polymenorrhea, in primordial follicle pool; b) Accelerated atresia of follicles; c) and metrorrhagia. Defective maturation/recruitment of primordial follicles (Figure 1).29 Furthermore, accelerated follicular atresia can be because 4. POI is an extreme state of total primordial follicle depletion; of changed apoptosis rate, defective follicle maturation blocking an irreversible state characterized by anovulation, amenor- and abnormalities in primordial follicle activation that causes rhea, infertility, and elevated gonadotropin levels. decreased number of available functional follicles/accelerated

Figure 1: (A) Normal Physiology of Foloocular Development. (B) Mechanism of Origin of Premature Ovarian Insuf- ficiency.29

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ISSN 2380-3940 http://dx.doi.org/10.17140/WHOJ-3-121 atresia.30,31 Trisomy

Hence, factors that initiate such mechanisms are highly Trisomy affects 1 in 1000 women.12,18 Trisomy X females usu- heterogeneous and can be a result of, genetic mutations, chro- ally have normal ovarian function, but in some, it may manifest mosomal, infectious, autoimmune, metabolic and iatrogenic fac- as early menopause, secondary amenorrhea, oligomenorrhea.10,38 tors.18,29 Around 10% of females have mosaicism with 46, XX/47, XXX or 45, X/47, XXX karyotypes. Manifestations depend on time AETIOLOGICAL FACTORS at which causing events occurred.10 Ovarian failure in females with 47, XXX (mosaic/non-mosiac) can be due to meiotic in- Genetic Factors adequacy of three X chromosomes, which is still unproven.10,34 However, cytogenetic studies in women with POI have shown Genetic factors are most commonly responsible for POI ac- that trisomy X (mosaic/non-mosaic patterns) have very low in- counting for 7% of all cases.3,5,32 X chromosome is most com- cidence of POI.10,39,40 monly affected, but autosomal involvement is also common.18,33 Aneuploidies and rearrangements are most commonly reported Fragile X Syndrome with POI34 (Figure 2).29 Fragile X syndrome is an X-linked dominant genetic condition X CHROMOSOME characterised by expansion of trinucleotide repeat41 with preva- lence of 1/6000 in females and 1/4000 in males.42,43 It is a com- Monosomy (45 X) mon cause of hereditary mental retardation and developmental delay.43,44 Fragile X mental retardation 1 (FMR1) gene is located Terminal deletions of long arm of X chromosome result in on X chromosome at Xq27.3. There is expansion of CGG trinu- primary amenorrhea and absence of breast development in all cleotide repeats in 5′ untranslated region of first exon of FMR1 cases.12,35 Total or near total absence of single X chromosome,18 gene. Affected females show >200 CGG repeats, as compared known as Turner’s syndrome affects around 1 in 2500 live fe- to normal (5-54 CGG repeats). This expansion of >200 repeats male births and is usually associated with ovarian dysgenesis causes methylation-coupled silencing of FMR1 gene resulting in leading to primary amenorrhea. However, 3-5% of such females loss of FMR-protein which is important for brain development with Turner mosaic karyotype can menstruate and even develop in prenatal and postnatal period.41,43,45 secondary sexual characteristics. Turner syndrome is associated with 4-5% POI cases.12,36,37 Recently, it was reported that higher number of CGG

Figure 2: Genes involved in Pathogenesis of Premature Ovarian Insufficiency.29

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ISSN 2380-3940 http://dx.doi.org/10.17140/WHOJ-3-121 repeats (>30-40) can be used to detect premature ovarian aging mediated immunity, etc.43,75,83,87,88 and POI in infertile women.43,46 An estimated 16-26% of female with FMR1 premutation carriers develop POI,43,47,48 whereas There are three main types of autoimmune POI: Adre- only 2% of normal women develop isolated POI.49 They are also nal autoimmune POI, non-adrenal autoimmune POI and isolated known to develop tremor-ataxia syndrome,50 mild neuro-cogni- idiopathic POI.43,88,89 Autoimmune causes in pathogenesis of POI tive dysfunction.51 It was also reported that paternally inherited is characterised by presence of autoantibodies directed towards Fragile X premutations were more likely to be associated with the ovarian tissue.84,90,91 These AOAs can be detected in the se- POI as compared to maternally inherited permutations.52 rum of affected females before clinical onset of POI.92 These antibodies bind to various steroid hormone-producing cells8,14, Bone Morphogenetic Protein 15 Gene (BMP15) 82,93,94 like adrenal cortex cells, theca cells of ovary, placental syncytiotrophoblast cells, and are known as steroid cell antibod- Bone morphogenetic proteins (BMPs) are proteins belonging ies (StCAs).82 They also bind to gonadotropins and their recep- to transforming growth factor-β (TGF-β) superfamily, which tors,95-97 zona pellucid,98 oocyte,99 corpus luteum,84,100 and can act play an important role in oocyte-specific growth/differentia- as markers of ovarian autoimmunity.82 tion factors that help in follicle maturation and granulosa cell growth.18,29,53,54 BMP15 gene is located on the short arm of Chro- Furthermore, it was observed that POI has strong as- mosome X (Xp11.2) within ‘POI critical region’.18,29,55 BMP15 sociation with autoimmune Addison’s disease. Around 60-87% mutations are associated with 1.5-12% of POI cases.1,56-60 This cases of POI have Addison’s disease.14,82,90,93,101 There are two defect is an unusual example of X-linked disease in which af- types of autoimmune polyendocrine syndromes (APS)5,74,75 fected females inherit mutation from their unaffected father.1,56 strongly associated with POI. Type 1 APS [autoimmune poly- endocrinopathy candidiasis ectodermal dystrophy (APECED)] Autosomal Genes characterized by combination of hypoparathyroidism, adrenal failure, and chronic mucocutaneous candidiasis. It is usually Genetic studies have shown various isolated gene defects associ- seen in children and is associated with POI in 60% cases pre- ated with POI, which are: senting as primary amenorrhoea. Type II APS is characterised by autoimmune Addison’s disease with adrenal insufficiency a) Estrogen receptor (ER-α and ER-β) mutations,12,35 and other autoimmune illnesses without hypoparathyroidism.5,74 b) FSH receptor mutations (FSHr),61,62 associated with <1% POI It usually occurs between the third to fourth decades of life and cases.1,32, 60,63 is associated with POI in 25-40% cases.14,82,90,93,101 Other autoim- c) LH receptor mutations (LHr)64 associated with <1% POI cas- mune conditions commonly associated with POI are: hypothy- es.1,32,60,63 roidism,102-104 autoimmune adrenal insufficiency,105 hypoparathy- d) FOXL2 mutations: Occurs with either blepharophimosis-pto- roidism,79 type 1 diabetes mellitus, hypophysitis, autoimmune sis-epicanthus inversus syndrome (BPES) type 1 (without POI) haemolytic anaemia, celiac disease, inflammatory bowel diseas- or BPES type 2 (with POI), known as POI-3.1,65,66 es, glomerulonephritis,5 Sjogren’s syndrome106 and myasthenia e) Steroidogenic factor 1 (NR5A1) mutation.12,35 gravis.89 f) CYP19A1 mutation.12,35,67,68 g) Inhibin A gene mutation associated with 5% of POI cases.60,69 Iatrogenic h) NOBOX gene: Newborn ovary homeobox gene (NOBOX) plays role in initial phases of follicular maturation70 and is rarely Iatrogenic causes for POI are increasing due to rise in incidence associated with POI.71,72 of various gynaecological cancers and their successful treatment.107,108 Oocyte is highly radiosensitive and responds to even Despite several genes shown to be associated with POI, 2 Gray dose of radiotherapy.43,109 Hence, an ovarian radiotherapy the exact mechanism still remains uncertain.54,56,65,73 dose of ≥6 Gray results in ovarian insufficiency in almost all females over 40 years of age.110 Effect of radiotherapy on ova- Autoimmune Factors ries is dependent on dose, age, and radiation therapy field.43,111, 112 Chemotherapy also causes ovarian insufficiency but exact Autoimmunity is characterized by auto-reactive lymphocytosis, mechanisms are not clear; however, it is well known that chemo- organ and non-organ-specific autoantibodies.74,75 It accounts for therapeutic agents affect granulosa cell functions and oocytes, 4-30% of POI cases1,8,76-82 and is characterised by presence of an- ultimately causing ovarian insufficiency.43,113 Major predictive tiovarian antibodies (AOAs), lymphocytic oophoritis on histo- factors for development of ovarian insufficiency after chemo- pathological examination, in association with other autoimmune therapy are; age, class, dose of chemotherapeutic agent, con- conditions.82-86 Exact mechanism of autoimmune POI remains current use of radiotherapy, etc.43,108,114 It has been reported that obscure and may be due to genetic and or environmental factors use of alkylating agents (N-mustard, L-phenylalanine mustard, that are responsible for initiating immune response.43,75,83,87,88 Im- Chlorambucil, Busulfan, and Cyclophosphamide) are strongly portant factors involved are: Major histocompatibility complex associated with POI (40%).12 antigen (HLA), cytokines, cell-mediated immunity, antibody-

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Furthermore, it has been reported that ovarian drilling and persistent.125 for polycystic ovarian syndrome and chocolate cysts removal for endometriosis are associated with early menopause.12,115 Recent Diagnosis and Assessment literature reports that uterine artery embolization also leads to POI by affecting ovarian vascular supply.43,116 Hence, it was ob- Diagnosis of POI can be easily made on clinical presentation, served that almost any pelvic surgery, be it ovarian cyst removal in woman <40 years of age with amenorrhea or oligomenorrhea or hysterectomy–can affect ovaries and lead to POI, by affect- of 4-6 months with two measurements of elevated FSH levels. ing vascular supply or by causing inflammation in pelvic area.117 Final diagnosis can be made on certain investigations which in- Studies have shown that in some cases of POI, ovarian function clude125: may return spontaneously many years after chemotherapy and/ 118,119 or radiotherapy and many successful pregnancies can also Gonadotropin Levels: Both FSH and LH are elevated in women 43 occur in such women. with POI (hypergonadotropic amenorrhea). Elevated FSH levels are more significant than LH. High FSH levels are considered Infectious and Toxic agents as gold standard for diagnosis of POI and values >25 U/L on two occasions, more than 4 weeks apart is indicative of ovarian Till date there are no direct evidences available that suggest insufficiency.125 correlation between infections and POI, but studies report that Mumps oophoritis may be related to development of POI. True reason of post-oophritis ovarian failure is unknown.5,43,120 In vast Low Estrogen levels: Estradiol (E2) levels <50 pg/ml is typi- 78 majority of affected women, return of ovarian function occurs cally observed in women with POI. Low estradiol levels in following recovery.18,43 Another infectious agent and its treat- combination with high FSH and LH levels are diagnostic of POI. ment that can be linked with POI is HIV infection.5,121 It has been reported that around 3.5% of females with POI have a history Antimullerian Hormone (AMH): AMH is homodimeric gly- of infections like varicella, tuberculosis shigellosis, malaria and coprotein consisting of two subunits,129,130 and is produced by cytomegalovirus.7,43,80 granulosa cells of growing follicles.131 It regulates early follicular recruitment from primordial pool132 and is a good reflector Amongst the various toxins that are strongly associated of ovarian reserve.133-135 AMH levels are usually very low or with POI, smoking is one major toxin. It was found that there undetectable in women with POI.136 Hence, AMH testing may is an inverse relationship between number of cigarettes smoked become important diagnostic tool for assessment of ovarian re- per day and age at menopause.43,122 Smoking causes alteration of serve before and after chemotherapy in young women with pel- ovarian function, and leads to early menopause in female who vic cancers, before and after ovarian surgery, and for females at smoke as compared to non-smokers.43,123 high risk of POI.137,138

Other toxins that commonly affect ovarian functions Inhibin B: It is produced by granulosa cells of growing fol- and can lead to POI are: Polycyclic aromatic hydrocarbons licles,139 but its levels show significant variability between men- (PaHs), toxic chemicals in tobacco, heavy metals, insecticides, strual cycles. Hence, it is usually not recommended for diagno- plastics and industrial chemicals, but exact underlying mecha- sis of POI.138 nism is unclear.5,18 Once diagnosis of POI is made, other investigations include: Clinical Course • Karyotyping and fragile X mental retardation 1 (FMR-1) pre- Women with POI are typically observed with secondary amenor- mutation for genetic cause8 rhea/menopause, many a times preceded by irregular menstrual • Screening for autoimmune diseases like anti-adrenal, anti- cycle at age <40 years.20,78 In few women with primary amenor- 21-hydroxylase,8 anti-thyroid peroxidase, anti-thyroglobulin rhea, the cause can be an underlying chromosomal abnormali- antibodies125 and AOA are recommended. ty.20 Other characteristic symptoms include hot flushes and night sweats20,124; these are mainly due to estrogen deficiency.118,125 Vaginal symptoms include dyspareunia and dryness, which can Future Fertility be distressing for women.125,126 In addition to these, women also suffer from sleep disturbances, mood swings, lack of concen- Around 5-10% of women with POI conceive spontaneously tration, depression, loss of libido, dry eyes,127 altered urinary due to fluctuations in ovarian functions.12,125,140 Till date no clear frequency and lack of energy.117,125 These symptoms are usually guidelines or drugs are available that can cause follicular devel- transient and are mainly due to changes in ovarian functions (es- opment or increase fertility in women with POI.125 Various stud- trogen withdrawal rather than deficiency) that result from spon- ies have tried to examine the role of ovulation inducing drugs, taneous onset of POI.125,128 Furthermore, it was observed that in gonadotrophins, glucocorticoids, GnRH agonists and antago- women with surgically induced POI, symptoms are more severe nists,141 but no clear advantage has been observed.12

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However, fertility preservation techniques can be con- before planning for hysterectomy and/or oophorectomy in wom- sidered for women at risk of developing POI due to disease or en <50 years, especially for prophylactic reasons.125 its management. Considerably high rates of natural pregnancies were reported in such women who underwent fertility preser- Sexual and Genito-urinary Functions vation pre-treatment.125,142 Another way of improving fertility in women with POI due to sterilizing surgeries is replacement of In most women with POI, sexual problems are due to physiolog- cryopreserved ovarian tissue, but this has been studied in very ical stress, or secondary reaction to emotional stress of diagnosis few cases.125,143 and infertility resulting from the disease.161 Furthermore, fertility treatment has unpredictable outcomes which leads to emotional Recent advances have shown that oocyte donation is stress and affect sexual functions in the long run.125,162 Hence, to another option for women with POI desiring pregnancy.125 Such hold POI as the sole cause for sexual dysfunction may be incor- a successful pregnancy was first reported in 1984144 and since rect, also there are no direct evidences to evaluate effects of POI then it has become a ‘routine’ treatment. on sexuality.163

Long-term Consequences of POI /Premature Menopause Most common symptoms are those related to estrogen Bone Health deficiency, which include vasomotor symptoms, sleep - distur bances, depression, fatigue, loss of libido, vaginal dryness and Estrogen is known for its beneficial effects on bone growth. It dyspareunia.125,164 is responsible for increased bone remodelling and hence its deficiency is associated with bone loss, decreased mineral density Endocrine Diseases and fracture risk, as seen after natural menopause.145,146 Net bone 147 loss after menopause is usually 2-3% per year. Effect of es- Women with POI are prone to develop endocrine disorders later trogen deficiency on bone in women with POI is one of most in their life. Around 20% with idiopathic POI develop hypothy- clearly recognized adverse effects of POI. It usually remains roidism and most commonly Hashimoto thyroiditis.23 They also asymptomatic for many years, until fragility fracture happens. carry high risk of developing adrenal insufficiency.138 Furthermore, depending on degree and duration of estrogen deficiency, women with POI develop reduced bone mineral density Future Perspectives earlier as compared to normal females.148,149 An estimated 8-14% of women with POI suffer from osteoporosis148 as compared to Most recent studies have shown the role of stem cells in the normal females.150 treatment of POI and have reported that oocytes can be gener- ated from embryonic stem cells (ESCs).165,166 These ESCs are in- Cardiovascular duced into primordial germ cells which are then aggregated with somatic cells of female embryonic gonads for fertilisation.166,167 Estrogen has cardio-protective effects and its early loss leads to increased risk of cardio-vascular mortality.138,151 Hence, women Other pluripotent cells that have been studied for use with POI are associated with high risk of cardio-vascular mortal- include, mesenchymal stem cells (MSCs) used for repairing ity.78,125,138,151 Various researches have proven that women with damaged ovaries induced by chemotherapy.168 Umbilical cord spontaneous POI suffer early onset coronary heart disease152 and mesenchymal stem cells (UCMSCs) can also be used with ad- are at increased risk of dying from coronary vascular diseases vantage of little or no immune rejection.169 Adipose-derived stem (CVDs).125,153,154 Furthermore it has been observed that women cells (ADSCs) are another type of MSC that can be differentiated with pre-menopausal estrogen deficiency develop signs of en- into multiple cell types.170 dothelial dysfunction155 and premature atherosclerosis very early.125,156 It is well proven that estrogen plays an important role Bone marrow transplantation has also been studied for in ventricular contractile function,125,157 decreases insulin resis- use in women with poor ovarian function after long-term che- tance125,158 and protects against lipid peroxidation, thereby play- motherapy.166,171 Hence, it is possible that with the latest research ing an important role in cardio-protection. and advancement, ovarian aging may become reversible in the future, especially in women with POI.172 Cognitive and Neurological Health

Few studies have observed the effects of POI on neurological ACKNOWLEDGEMENT health of women.125 POI, especially the one resulting from bilateral oophorectomy before onset of natural menopause, increases I acknowledge and thank Dr. Namit Kant Singh for his advice risk of cognitive impairment/dementia. This risk is found to be and expertise. inversely proportional to the age at which oophorectomy is per- formed.12,159,160 Such women are also prone to develop Parkin- CONFLICTS OF INTEREST sonism later in their life.12,159,160 Hence, it is very important to explain all possible detrimental effects on neurological health There are no conflicts of interest.

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